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Herpes Simplex VirusPhase 1NCT00942084

A Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants (PTN_Acyclo)

A Phase 1 study testing Acyclovir in people with Herpes Simplex Virus and Neonatal Sepsis, run by Phillip Brian Smith at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Acyclovir is a drug used to treat herpes simplex virus (HSV) infections in babies. Appropriate dosing of acyclovir is known for adults and children but acyclovir has not been adequately studied in full-term or premature neonates. Read more about this study

Who is it for?
Ages Up to 45 days
Conditions the study is for
Herpes Simplex Virus, Neonatal Sepsis
What is being tested?
Acyclovir
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
32 participants
Where
3 sitesUnited States
Study dates
Sep 2011to Jun 2012
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 45 days
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • < 45 days of age at the time of initial study drug administration.
  • Sufficient venous access to permit administration of study medication.
  • Availability and willingness of the parent/legal guardian to provide written informed consent.
  • Suspected HSV sepsis OR At least two (2) of the following
  • Signs of sepsis AND negative blood cultures for >24 hours7
  • Respiratory distress8
Show all 13Show fewer
  • Lethargy8
  • Fever ≥ 38.0°C7
  • Skin lesions7,8
  • Seizures (clinical OR EEG confirmed)7
  • Irritability7
  • AST OR ALT >2 X upper limit of normal7,8
  • >20 WBCs/µL or >500 RBCs/µL7

Who cannot join

  • History of anaphylaxis attributed to acyclovir.
  • Serum creatinine >1.7 mg/dL.
  • Urine output <0.5 mL/kg/hour over the previous 12 hours
  • Previous participation in the study.
  • Concomitant condition, which in the opinion of the investigator would preclude a participant's participation in the study

Trial locations and contacts

3 sites in 1 country.

United States3 sites
  • Duke University

    Durham, North Carolina, 27713

  • Tulane School of Medicine

    New Orleans, Louisiana, 70112

  • Wesely Medical Center

    Wichita, Kansas, 67214-4976

Other trials in United States

About this study

Official title: An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants

Acyclovir is a drug used to treat herpes simplex virus (HSV) infections in babies. Appropriate dosing of acyclovir is known for adults and children but acyclovir has not been adequately studied in full-term or premature neonates. HSV is a very serious infection in babies <6 months of age and often results in death or profound mental retardation. HSV leads to profound mental retardation in young infants because the virus attacks the central nervous system.

The investigators hypothesize that the currently recommended dose of acyclovir is inadequate to produce adequate blood levels to combat herpes simplex infection. The investigators propose to study acyclovir levels in the blood of babies who are placed on acyclovir to treat a suspected HSV infection. This will allow them to determine the appropriate dose in premature infants. This is an unmet public health need because it is likely that the drug behaves differently in premature infants than it does in term infants and older children. Premature babies have more body water and less body tissue. Their kidneys are more immature and do not function as well as full term infants. Premature neonates are also at the greatest risk from herpes infection because they have poorly functioning immature immune systems. Early and appropriate treatment with acyclovir has resulted in improved outcome in term infants.

Read the detailed description

Neonatal herpes infection carries a major risk of death if untreated. Prognosis is related to disease extent and timing of therapy, making early diagnosis crucial. Mortality in the pre-antiviral era was 90% for disseminated disease and 50% for central nervous system (CNS) disease. Institution of high-dose (60 mg/kg/day) antiviral therapy with acyclovir has reduced mortality to 31% for disseminated disease and 6% for CNS disease.1 Although acyclovir has reduced mortality dramatically, morbidity remains high.

Study population: Infants < 45 days postnatal age, suspected to have a systemic infection divided into groups by gestational and postnatal age:

Group-1: 23-29 weeks gestational age, <14 days postnatal age Group-2: 23-29 weeks gestational age, 14-44 days postnatal age Group-3: 30-34 weeks gestational age, <45 days postnatal age

Intravenous acyclovir will be administered for 3 days.

Timing of PK sample collection will be with respect to the end of each IV infusion. Timed PK sampling will be drawn at doses 1, and doses 5, 6, 7, 8, or 9.

Dose 1:

0-15 minutes after completion of the 1st dose; Within 30 minutes prior to administration of 2nd dose

Steady state [doses 5 or 6 (groups 1 and 2), doses 8 or 9 (group 3)]:

Within 30 minutes prior to dose; 0-15 minutes after completion of the dose; 2-3 hours after completion of the dose; Within 30 minutes prior to administration of the next dose

Last dose:

6-7 hours after the last dose (groups 1 and 2)and 10-11 hours after the last dose (group 3)

Being tested
Acyclovir
Keywords
HSV, Acyclovir, Pharmacokinetics, Neonate, Premature, Sepsis
Medical subject headings
Herpes Simplex, Neonatal Sepsis, Premature Birth, Sepsis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AcyclovirDrug

    Protocol V2 \& up: Acyclovir 7mg/ml to be administered IV at 10 mg/kg IV q12 or 20 mg/kg IV q12 or 20 mg/kg IV q8 for a total of 6-9 doses(3 days).

    Protocol V1: Acyclovir 5 mg/mL to be administered IV at 500 mg/m2 IV q8h for a total of approximately 15 doses (10 days).

Study groups in NCT00942084
Study groupRoleWhat they receive
Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12Active comparatorGestational Age 23-29 weeks Postnatal Age < 14 days Dosage 10 mg/kg IV q12 Number of Infants 8
Receives: Drug: Acyclovir
Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12Active comparatorGestational Age 23-29 weeks Postnatal Age 14-44 days Dosage 20 mg/kg IV q12 Number of Infants 8
Receives: Drug: Acyclovir
Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8Active comparatorGestational Age 30-34 weeks Postnatal Age <45 days Dosage 20 mg/kg IV q8 Number of Infants 4
Receives: Drug: Acyclovir
Protocol V1-Grps1-4-Acyclo 500 mg/m2 IVq8hOtherAll patients in protocol V1 were to be dosed with 500 mg/m2 IV q8h. Protocol V1 Group 1: Gestational Age: 23-29 Weeks; PNA: <14 days; Protocol V1 Group 2: Gestational Age: 30-42 Weeks; PNA: <14 days; Protocol V1 Group 3: Gestational Age: 23-29 Weeks; PNA: 14-60 days; Protocol V1 Group 4: Gestational Age: 30-42 Weeks; PNA: 14-60 days
Receives: Drug: Acyclovir

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clearance (CL)

    Timeframe:

    Version 1:0-5 min,2-4 hrs,6-8 hrs post doses 1 and 5-15; prior to doses 5-15 Version 2:0-15 min post doses 1 and 5-15; within 30 min prior to doses 2 and 5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose

    Measured: V1:0-5 min,2-4 hrs,6-8 hrs post Doses 1&5-15;prior to doses 5-15; V2:0-15 min post doses 1&5-15; within 30 min prior to doses 2&5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose

  2. Volume of Distribution (V)

    Measured: up to 3 days of study drug administration and 10 days of safety monitoring

  3. Half-life (T1/2)

    Measured: up to 3 days of study drug administration and 10 days of safety monitoring

  4. Maximum Steady State Concentration (Cmaxss)

    Measured: up to 3 dasy of study drug administration and 10 days of safety monitoring

  5. Steady State Concentration at 50% of the Dosing Interval (C50ss)

    Measured: up to 3 days of study drug administration and 10 days of safety monitoring

  6. Minimum Steady State Concentration (Cminss)

    Measured: up to 3 days of study drug administration and 10 days of safety monitoring

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Jul 2009 (estimated)
  2. Study startSep 2011
  3. Primary completionJun 2012
  4. Study completionJun 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
32 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00942084
Sponsor's protocol ID
Pro00028772
Status last verified
Dec 2018
First submitted
17 Jul 2009
Last updated
8 Jan 2019
Data monitoring committee
Yes

Publications

  • Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002 Jan;13(1):6-11. doi: 10.1053/spid.2002.29752.

    PubMed 12118847
  • Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Weller S, Soong SJ, Kiell J, Lakeman FD, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001 Aug;108(2):230-8. doi: 10.1542/peds.108.2.230.

    PubMed 11483782
  • Lietman PS. Acyclovir clinical pharmacology. An overview. Am J Med. 1982 Jul 20;73(1A):193-6. doi: 10.1016/0002-9343(82)90089-4.

    PubMed 7048912
  • Englund JA, Fletcher CV, Balfour HH Jr. Acyclovir therapy in neonates. J Pediatr. 1991 Jul;119(1 Pt 1):129-35. doi: 10.1016/s0022-3476(05)81053-4.

    PubMed 2066845
  • Blum MR, Liao SH, de Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. Am J Med. 1982 Jul 20;73(1A):186-92. doi: 10.1016/0002-9343(82)90088-2.

    PubMed 7048911
  • Hintz M, Connor JD, Spector SA, Blum MR, Keeney RE, Yeager AS. Neonatal acyclovir pharmacokinetics in patients with herpes virus infections. Am J Med. 1982 Jul 20;73(1A):210-4. doi: 10.1016/0002-9343(82)90093-6.

    PubMed 6285713
  • Yeager AS. Use of acyclovir in premature and term neonates. Am J Med. 1982 Jul 20;73(1A):205-9. doi: 10.1016/0002-9343(82)90092-4.

    PubMed 6285712
  • Pickering LK. Red Book. 28th ed. Elk Grove Village, Illinois: American Academy of Pediatrics; 2009.

  • Kimberlin DW. When should you initiate acyclovir therapy in a neonate? J Pediatr. 2008 Aug;153(2):155-6. doi: 10.1016/j.jpeds.2008.04.027. No abstract available.

    PubMed 18639724
  • Brigden D, Bye A, Fowle AS, Rogers H. Human pharmacokinetics of acyclovir (an antiviral agent) following rapid intravenous injection. J Antimicrob Chemother. 1981 Apr;7(4):399-404. doi: 10.1093/jac/7.4.399. No abstract available.

    PubMed 7251524
  • Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. J Infect Dis. 1988 Feb;157(2):385-8. doi: 10.1093/infdis/157.2.385. No abstract available.

    PubMed 3335815
  • Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009 Jan;24(1):67-76. doi: 10.1007/s00467-008-0997-5. Epub 2008 Oct 10.

    PubMed 18846389

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Acyclovir in people with Herpes Simplex Virus and Neonatal Sepsis, run by Phillip Brian Smith at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Jan 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clearance (CL) (time frame: V1:0-5 min,2-4 hrs,6-8 hrs post Doses 1&5-15;prior to doses 5-15; V2:0-15 min post doses 1&5-15; within 30 min prior to doses 2&5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00942084, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jan 2019.

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